PROJECT SUMMARY Severe sepsis leads to systemic inflammation, wherein activation of the complement and coagulation systems play critical roles. Evidence from patients and animal models suggest that sepsis is a multi-stage, multi- factorial disease in which the early fulminate inflammatory response to the invading bacteria leads to hypo- perfusion and ischemia reperfusion (IR) injury that evolves to multiple organ failure (MOF) and ultimately to death. The objectives of this proposal are to investigate if the crosstalk between the coagulation and complement activation pathways during sepsis caused by two most common pathogens, Escherichia coli and Staphylococcus aureus contribute to microthrombosis, vascular dysfunction, organ failure and death; and, whether inhibition of complement activation at the C5 level could prevent MOF and improve the outcome of sepsis. We will use clinically relevant models of sepsis to address the following objectives: (i) determine the role of complement activation during the bacteremic stage of E. coli sepsis and characterize the protective effects of early treatments with C5 inhibitors; (ii) determine the effect of complement activation on platelet clearance in sepsis; (iii) determine if delayed treatment with C5 inhibitors provides organ protection and survival benefit in a model of sepsis-induced progressive organ failure. Successful completion of these aims will determine: (i) whether timed complement inhibition at the C5 level could be used as an effective therapy for sepsis-induced MOF; (ii) if deposition of complement fragments on platelets contribute to their removal from circulation; (iii) which is the optimum therapeutic time window for complement inhibition to attenuate the disease progression without affecting bacteria clearance. Altogether, our project will combine basic and preclinical research to verify novel hypotheses on the pathophysiology of Gram-negative and Gram-positive sepsis and test innovative approaches, which, in the long-term may save lives from a deadly disease with no specific cure. !